Pharmaceutical composition for reducing generation of nitrosamine impurity of vonoprazan, and preparation method therefor

Abstract

Disclosed are: a pharmaceutical composition capable of inhibiting the generation of a nitrosamine impurity of a vonoprazan drug product by means of an antioxidant; and a preparation method therefor.

Description

DESCRIPTIONInvention TitlePHARMACEUTICAL COMPOSITION FOR REDUCING GENERATION OF NITROSAMINE IMPURITY OF VONOPRAZAN, AND PREPARATION METHOD THEREFORTechnical Field

[0001] The present invention relates to a pharmaceutical composition for reducing the formation of N-nitroso vonoprazan, which is a nitrosamine impurity of vonoprazan, and a method for preparing the same. More specifically, the present invention relates to a pharmaceutical composition comprising an antioxidant and capable of reducing the formation of the nitrosamine impurity, and a method for preparing the same.Background Art

[0002] Gastroesophageal reflux disease (GERD), the most common type of digestive disease, is a type of gastrointestinal disease caused by excessive gastric acid secretion or hypersensitivity to gastric acid. Proton pump inhibitors (PPIs) and potassium competitive acid blockers (P-CABs), which are used to treat gastroesophageal reflux disease, exhibit potent gastric acid secretion inhibitory effects and are widely used to treat various gastric acid-related diseases.

[0003] Vonoprazan, one of the P-CAB class drugs, inhibits gastric acid secretion by competing with potassium ions for binding to ATPase (proton pump), an enzyme that secretes hydrogen ions from the gastric parietal cells into the gastric lumen. Unlike PPI class drugs, vonoprazan does not require conversion into an activated form by gastric acid but directly inhibits the proton pump, thus exhibiting a rapid gastric acid secretion inhibitory effect. In addition, compared to PPI class drugs, vonoprazan is effective in controlling nocturnal acid secretion because it has a longer duration of action due to its longer half-life, and it has the advantage of being able to be used in combination with other drugs because it has fewer interactions with other drugs.

[0004] However, vonoprazan is a pyrrole derivative compound (1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate) as represented by Chemical Formula 1 below, which contains a secondary amine, and thus has the potential problem of forming N-nitroso vonoprazan, which is a nitrosamine impurity represented by Chemical Formula 2 below.

[0005] [Chemical Formula 1]

[0006]

[0007] [Chemical Formula 2]

[0008]

[0009] Nitrosamine impurities are carcinogenic substances. Starting in June 2018, when it was discovered that nitrosamine impurities were present in angiotensin II receptor blocker (ARB) drugs such as valsartan, N-nitrosodimethylamine (NDMA) impurities were subsequently detected in the gastric acid secretion inhibitors ranitidine and nizatidine around 2019, leading to sales suspension and recall. Additionally, from late 2019 to early 2020, N-nitrosodimethylamine (NDMA) impurities were also detected in metformin, a type 2 diabetes drug, leading to recall. As nitrosamine impurities have repeatedly been found in various pharmaceuticals, guidelines and regulations aimed at reducing the risk caused by nitrosamine impurities have been continuously released.

[0010] Nitrosamine impurities may be formed by the nitrosation reaction between secondary, tertiary, or quaternary amines present in active pharmaceutical ingredients (APIs) and nitrites. In the case of finished pharmaceutical products, nitrosamine impurities may be generated by various causes, such as the manufacturing process of active pharmaceutical ingredients and / or nitrites present in excipients contained in the finished pharmaceutical products, as well as the manufacturing process, temperature, humidity, and acidic environment. The U.S. Food and Drug Administration (FDA) has classified nitrosamine impurities into N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosomethylphenylamine (NMPA), N-nitrosodiisopropylamine (NDIPA), N-nitrosoisopropylethylamine (NIPEA), N-nitrosodibutylamine (NDBA), and N-nitroso-N-methyl-4-aminobutyric acid (NMBA); in pharmaceuticals, N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitroso-N-methyl-4-aminobutyric acid (NMBA), N-nitrosoisopropylethylamine (NIPEA), and N-nitrosomethylphenylamine (NMPA) have been found.

[0011] Therefore, various studies have been actively conducted to reduce the formation of nitrosamine impurities in vonoprazan, such as improving the synthesis pathway (avoiding reactions that induce the formation of nitrosamine impurities or minimizing the formation of impurities through the development of alternative pathways) and optimizing the management of raw materials and intermediates, but none of these approaches have yielded any significant results.

[0012] [Prior Art Documents]

[0013] [Patent Documents]

[0014] (Patent Document 1) International Patent Publication No. WO 2019 / 013310DISCLOSURETechnical Problem

[0015] An object of the present invention is to provide a pharmaceutical composition capable of inhibiting the formation of nitrosamine impurities during the manufacture and storage of a finished pharmaceutical product containing vonoprazan, and a method for preparing the same.

[0016] More specifically, the present invention provides a pharmaceutical composition comprising vonoprazan or a pharmaceutically acceptable salt thereof as an active ingredient, which may minimize the formation of N-nitroso vonoprazan, a nitrosamine impurity of vonoprazan, during the manufacturing process of the finished pharmaceutical product, and reduce the formation of N-nitroso vonoprazan during storage of the finished pharmaceutical product, and a method for preparing the same.

[0017] To achieve the above object, the pharmaceutical composition is characterized by comprising an antioxidant.Technical Solution

[0018] In order to solve the above problem, the present invention discloses the following means.

[0019] In one aspect, the present invention provides a pharmaceutical composition comprising vonoprazan or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the pharmaceutical composition comprises an antioxidant and inhibits the formation of N-nitroso vonoprazan, a nitrosamine impurity of vonoprazan.

[0020] In another aspect, the present invention provides a method for preparing a pharmaceutical composition comprising vonoprazan or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the method for preparing the pharmaceutical composition comprises performing a wet granulation or dry granulation process, wherein the wet granulation process comprises preparing a kneaded mixture, followed by drying the granules using a vacuum dryer or a fluidized bed dryer.Advantageous Effects

[0021] The present invention has the advantage of enhancing stability by inhibiting the formation of nitrosamine impurities in a finished pharmaceutical product containing vonoprazan during the manufacturing process or storage.

[0022] More specifically, the present invention may provide a pharmaceutical product in tablet form that, by comprising an antioxidant, may inhibit the formation of N-nitroso vonoprazan, a nitrosamine impurity generated by the secondary amine of vonoprazan during storage of the finished pharmaceutical product.

[0023] In addition, the present invention may provide a pharmaceutical product in tablet form having significantly reduced initial nitrosamine impurities by inhibiting the formation of N-nitroso vonoprazan, a nitrosamine impurity that may increase during the process of manufacturing a finished pharmaceutical product containing vonoprazan, through vacuum drying or fluidized bed drying.

[0024] Strict quality control standards must be applied to minimize the formation of nitrosamine impurities. However, according to the present invention, there is an advantage in that initial nitrosamine impurities during the manufacturing of a finished pharmaceutical product containing vonoprazan may be significantly reduced, thereby reducing the cost of quality control.

[0025] The effects of the present invention are not limited to the effects mentioned above, and various effects may be included within the scope obvious to those skilled in the art from the following description.Brief Descriptionof Drawings

[0026] FIG. 1 shows the results obtained by measuring N-nitroso vonoprazan formed when a mixture according to Example 5, which does not contain an antioxidant, and mixtures according to Examples 6 to 8, which contain an antioxidant, were stored under a storage condition of 60°C for 2 weeks, by liquid chromatography-mass spectrometry (LC-MS / MS).

[0027] FIG. 2 shows the results obtained by measuring N-nitroso vonoprazan formed when a film-coated tablet according to Example 9, which does not contain butylated hydroxyanisole, and film-coated tablets according to Examples 10 to 15, which have different butylated hydroxyanisole contents, were stored under a storage condition of 60°C for 4 weeks, by LC-MS / MS.Best Mode

[0028] Hereinafter, the present specification will be described in more detail.

[0029] The detailed description of the present specification is as follows. The terms used in the present specification are currently widely used general terms selected in consideration of their functions in the present invention, but they may change depending on the intents of those skilled in the art, precedents, or the advent of new technology. Additionally, in certain cases, there may be terms arbitrarily selected by the applicant, in which case their meanings will be described in a corresponding description part of the present invention. Accordingly, terms used in the present invention should be defined based on the meaning of the term and the entire contents of the present invention, rather than the mere name of the term.

[0030] Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meanings as understood by those skilled in the art to which the present disclosure pertains.

[0031] Terms such as those used in general and defined in dictionaries should be interpreted as having meanings identical to those specified in the context of related technology. Unless explicitly defined in the present application, the terms should not be interpreted as having ideal or excessively formal meanings.

[0032] The numerical range includes numerical values defined in the above range. Every maximum numerical limitation given throughout the present specification includes every lower numerical limitation, as if such lower numerical limitations were expressly written herein. Every minimum numerical limitation given throughout the present specification will include every higher numerical limitation, as if such higher numerical limitations were expressly written herein. Every numerical range given throughout this specification will include every narrower numerical range that falls within such broader numerical range, as if such narrower numerical ranges were all expressly written herein.

[0033] Hereinafter, each description and embodiment disclosed in the present invention may also be applied to other descriptions and embodiments. That is, all combinations of various elements disclosed in the present invention fall within the scope of the present invention. In addition, the scope of the present invention may not be considered to be limited by the specific description described below.

[0034] Expressions such as “comprising” as used in the present specification should be understood as open-ended terms that imply the possibility of including other embodiments.

[0035] During the development of a pharmaceutical product containing vonoprazan or a pharmaceutically acceptable salt thereof as an active ingredient, the inventors of the present invention have found that N-nitroso vonoprazan, a nitrosamine impurity, is formed by the secondary amine included in the structure of vonoprazan, and that its formation is promoted by heat.

[0036] Since nitrosamine impurities are known to be potential carcinogens, they are a critical issue regarding pharmaceutical safety. Thus, the inventors of the present invention have conducted studies to inhibit the formation of N-nitroso vonoprazan, a nitrosamine impurity of vonoprazan. Through these studies, the present inventors have found that if a pharmaceutical composition comprising vonoprazan or a pharmaceutically acceptable salt thereof as an active ingredient comprises an antioxidant, the nitrosation reaction with nitrite, a factor causing formation of the nitrosamine impurity, may be inhibited. Therefore, the present inventors have designed a pharmaceutical composition comprising an antioxidant, particularly a formulation in the form of a tablet (film-coated tablet), and have devised a method to minimize heat-induced processes that may accelerate the formation of the nitrosamine impurity during the manufacturing process. The present inventors have found that a finished pharmaceutical product in the form of a tablet (film-coated tablet) containing vonoprazan or a pharmaceutically acceptable salt thereof as an active ingredient inhibits the formation of N-nitroso vonoprazan when stored for 6 months under accelerated stability conditions (40°C / 75%), thereby completing the present invention.

[0037] In the present specification, the term “vonoprazan” may refer to vonoprazan or a pharmaceutically acceptable salt thereof. Accordingly, in the present specification, a pharmaceutical composition comprising vonoprazan and a method of preparing the same may refer to a pharmaceutical composition comprising vonoprazan or a pharmaceutically acceptable salt thereof and a method of preparing the same.

[0038] Hereinafter, the present invention will be described in detail.

[0039] Pharmaceutical composition in which the formation of N-nitroso vonoprazan, a nitrosamine impurity, is inhibited

[0040] In one aspect, the present invention discloses a pharmaceutical composition comprising vonoprazan or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the pharmaceutical composition comprises an antioxidant and inhibits the formation of N-nitroso vonoprazan, which is a nitrosamine impurity of vonoprazan.

[0041] In the present invention, the term “active ingredient” means vonoprazan or a pharmaceutically acceptable salt thereof for gastric ulcers, erosive gastroesophageal reflux disease, maintenance therapy after treatment of erosive gastroesophageal reflux disease, or prevention of recurrence of gastric ulcers or duodenal ulcers upon administration of non-steroidal anti-inflammatory drugs (NSAIDs), and may also be referred to as an active pharmaceutical ingredient (API).

[0042] In the present invention, the term “pharmaceutically acceptable salt” includes salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases. More specifically, in the present invention, the pharmaceutically acceptable salt of vonoprazan may be vonoprazan fumarate, vonoprazan succinate, vonoprazan benzoate, vonoprazan citrate, vonoprazan mesylate, vonoprazan tartrate, or vonoprazan besylate, and more specifically, may be vonoprazan fumarate.

[0043] In the present invention, vonoprazan fumarate can be easily synthesized chemically by a known synthesis method by a person skilled in the art and used, or a commercially produced product may be purchased and used.

[0044] In the present invention, the pharmaceutical composition is characterized by comprising an antioxidant, and has a technical significance in that the use of the antioxidant can inhibit the formation of a nitrosamine impurity that may be formed by the secondary amine of vonoprazan or a pharmaceutically acceptable salt thereof.

[0045] In the present invention, the amount of vonoprazan may be 10 mg or 20 mg as vonoprazan per unit dosage form (specifically, per tablet when the formulation of the pharmaceutical composition is a tablet or film-coated tablet), and may be 13.36 mg or 26.72 mg as vonoprazan fumarate.

[0046] In the present invention, the antioxidant that inhibits the formation of nitroso compounds may be, for example, any one or more selected from the group consisting of butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, ascorbic acid, α-tocopherol, L-cystine, glycine, and arginine, preferably butylated hydroxyanisole, without being limited thereto.

[0047] In the present invention, the above pharmaceutical composition may comprise 0.01 to 2 mg, preferably 0.5 to 2 mg, of butylated hydroxyanisole per unit dosage form, without being limited thereto.

[0048] Specifically, the amount of butylated hydroxyanisole may be 0.5 to 2 mg per unit dosage form when the pharmaceutical composition comprises 10 mg of vonoprazan per unit dosage form (specifically, per tablet when the formulation of the pharmaceutical composition is a tablet or film-coated tablet), and may be 1 to 2 mg per unit dosage form when the pharmaceutical composition comprises 20 mg of vonoprazan, without being limited thereto.

[0049] In the present invention, the above pharmaceutical composition comprises vonoprazan or a pharmaceutically acceptable salt thereof as an active ingredient and an antioxidant, and may further comprise any one or more pharmaceutical additives selected from among excipients, stabilizers, binders, disintegrants and lubricants, without being limited thereto.

[0050] In the present invention, the above “excipient” is a substance intended to increase productivity and stability and increase the volume or weight of the tablet. More specifically, the excipient may be any one or more selected from the group consisting of D-mannitol, lactose, silicified microcrystalline cellulose, and microcrystalline cellulose, without being limited thereto.

[0051] In the present invention, the above “stabilizer” is a substance that helps improve the stability and solubility of vonoprazan and stabilize the formulation. More specifically, the stabilizer may be fumaric acid, without being limited thereto.

[0052] In the present invention, the above binder may be any one or more selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxymethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, methyl cellulose, sodium methyl cellulose, polyvinyl alcohol, and polyvinyl pyrrolidone, without being limited thereto.

[0053] In the present invention, the above “disintegrant” is intended to improve the dissolution of the drug by promoting the disintegration of the formulation. More specifically, the disintegrant may be any one or more selected from the group consisting of crospovidone, croscarmellose sodium, and low-substituted hydroxypropyl cellulose, without being limited thereto.

[0054] In the present invention, the lubricant may be magnesium stearate, without being limited thereto.

[0055] In the present invention, the pharmaceutical composition may be a tablet or a film-coated tablet, without being limited thereto.

[0056] In the present invention, the above film-coated tablet may use a coating agent widely known in the art, specifically an Opadry coating agent, without being limited thereto.

[0057] In the present invention, the above pharmaceutical composition may be prepared by a wet granulation process or a dry granulation process, without being limited thereto.

[0058] In the present invention, the above wet granulation process may comprise preparing a kneaded mixture, followed by drying using a vacuum dryer at room temperature or a fluidized bed dryer at 30 to 60°C, without being limited thereto.

[0059] Here, “room temperature” is defined in the Korean Pharmacopoeia and refers to a specific temperature range of 1 to 30°C.

[0060] Method for preparing a pharmaceutical composition in which the formation of N-nitroso vonoprazan, a nitrosamine impurity, is inhibited

[0061] In another aspect, the present invention discloses a method for preparing a pharmaceutical composition comprising vonoprazan or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the method for preparing the pharmaceutical composition comprises performing a wet granulation or dry granulation process, wherein the wet granulation process comprises preparing a kneaded mixture, followed by drying the granules using a vacuum dryer or a fluidized bed dryer.

[0062] In the present invention, when the pharmaceutical composition is prepared by a wet granulation process, an antioxidant may be added during the process of preparing the kneaded mixture, without being limited thereto.

[0063] More specifically, when the kneaded mixture is dried in a hot air circulating tray dryer, the amount of nitrosamine impurities increases significantly, whereas when vacuum drying at room temperature or fluidized bed drying at 30 to 60°C according to the present invention is performed, there is an advantage in that the formation of nitrosamine impurities may be reduced. Therefore, the preparation method of the present invention is characterized in that, when the wet granulation process is performed, a tray drying method using hot air circulation is not applied.

[0064] In the present invention, when drying with a fluidized bed dryer is performed under a condition of 30 to 60°C, there is an advantage in that the time exposed to heat is reduced compared to that in tray drying, so that the formation of nitrosamine impurities that may occur during the preparation process is reduced.

[0065] Also, even in the case of dry granulation, there is no drying process, so there is an advantage of being able to reduce the formation of nitrosamine impurities during the preparation process.

[0066] Specifically, a method of preparing the pharmaceutical composition through a wet granulation process comprises: a step of mixing vonoprazan fumarate, D-mannitol, microcrystalline cellulose, and butylated hydroxyanisole in a high-speed stirrer and kneading the mixture with an aqueous solution of fumaric acid and hydroxypropyl cellulose; a step of drying the kneaded mixture using a vacuum dryer at room temperature or a fluidized bed dryer at 30 to 60°C, followed by sizing into granules; a step of post-mixing the sized granules with croscarmellose sodium and magnesium stearate, followed by compression into tablets; and a step of coating the uncoated tablets.

[0067] In addition, a method of preparing the pharmaceutical composition through a dry granulation process comprises: a step of mixing vonoprazan fumarate, D-mannitol, microcrystalline cellulose, hydroxypropyl cellulose and fumaric acid, and compressing the mixture using a roller compactor, followed by sizing into granules; a step of mixing the sized granules with croscarmellose sodium and magnesium stearate, followed by compression into tablets; and a step of coating the uncoated tablets.

[0068] The above-described contents regarding the pharmaceutical composition may all be applied to the method of preparing the pharmaceutical composition unless they are contradictory.

[0069] Hereinafter, the present invention will be described in more detail through examples and test examples. However, these examples and test examples are merely illustrative of the present invention and the scope of the present invention is not limited thereto.

[0070] Examples

[0071] Examples 1 to 4. Preparation of tablets (film-coated tablets) (wet granulation method / dry granulation method)

[0072] Example 1. Preparation I of tablets (film-coated tablets) (wet granulation method)

[0073] According to the composition shown in Table 1 below, vonoprazan fumarate, D-mannitol, and microcrystalline cellulose components, excluding croscarmellose sodium, magnesium stearate, and fumaric acid, were mixed in a high-speed stirrer and kneaded with an aqueous solution (binder solution) of fumaric acid and hydroxypropyl cellulose. The kneaded mixture was dried using a hot air circulating tray dryer at 50°C, and then sized into granules. The sized granules were mixed with croscarmellose sodium and magnesium stearate, and made into granules for tableting, which were then compressed into tablets, thereby preparing uncoated tablets. A coating solution (coating solvent: water) was sprayed onto the prepared uncoated tablets, thereby preparing film-coated tablets.

[0074] [Table 1]ComponentsAmount added (1T / mg)Vonoprazan fumarate (as vonoprazan)26.72(20.00)D-Mannitol169.18Microcrystalline cellulose10.00Hydroxypropyl cellulose3.00Fumaric acid0.10croscarmellose sodium3.00Magnesium stearate2.00Opadry7.00Tablet (film-coated tablet) weight221.00

[0075] Example 2. Preparation II of tablets (film-coated tablets) (wet granulation method)

[0076] Film-coated tablets were prepared by performing the same process as in Example 1 above, except that the drying of the kneaded mixture was performed using a vacuum dryer at room temperature instead of the hot air circulating tray dryer at 50°C.

[0077] Example 3. Preparation III of tablets (film-coated tablets) (wet granulation method)

[0078] Film-coated tablets were prepared by performing the same process as in Example 1 above, except that the drying of the kneaded mixture was performed using a fluidized bed dryer at 50°C instead of the hot air circulating tray dryer at 50°C.

[0079] Example 4. Preparation IV of tablets (film-coated tablets) (dry granulation method)

[0080] According to the composition described in Table 1 above, vonoprazan fumarate, D-mannitol, microcrystalline cellulose, hydroxypropyl cellulose, and fumaric acid components, excluding croscarmellose sodium and magnesium stearate, were mixed together, and then compressed using a roller compactor, followed by sizing into granules. The sized granules were mixed with croscarmellose sodium and magnesium stearate and made into granules for tableting, which were then compressed into tablets, thereby preparing uncoated tablets. A coating solution (coating solvent: water) was sprayed onto the prepared uncoated tablets, thereby preparing film-coated tablets.

[0081] Examples 5 to 8. Preparation of mixtures containing / not containing antioxidants

[0082] All components listed in the formulation of Table 2 below were weighed, simply mixed, and then stored at 60°C for 2 weeks. Next, N-nitroso vonoprazan was measured by LC-MS / MS. Butylated hydroxyanisole, butylated hydroxytoluene, and propyl gallate were selected as antioxidants, and the amount of each antioxidant was selected to be 5.55 μM and the antioxidants were added in equal molar amounts (Examples 6 to 8).

[0083] [Table 2]ComponentsExample 5(1T / mg)Example 6(1T / mg)Example 7(1T / mg)Example 8(1T / mg)Vonoprazan fumarate (as vonoprazan)26.72(20.00)26.72(20.00)26.72(20.00)26.72(20.00)D-Mannitol169.18169.18169.18169.18Microcrystalline cellulose10.0010.0010.0010.00Butylated hydroxyanisole-1.00--Butylated hydroxytoluene--1.22-Propyl gallate---1.18Hydroxypropyl cellulose3.003.003.003.00Fumaric acid0.100.100.100.10croscarmellose sodium3.003.003.003.00Magnesium stearate2.002.002.002.00Opadry7.007.007.007.00

[0084] Examples 9 to 15. Preparation of tablets (film-coated tablets) containing / not containing butylated hydroxyanisole (wet granulation method)

[0085] To determine the range in which butylated hydroxyanisole, an antioxidant contained in a tablet (film-coated tablet), can effectively inhibit N-nitroso vonoprazan, film-coated tablets were prepared using the components and amounts shown in Table 3 below.

[0086] More specifically, vonoprazan fumarate, D-mannitol, microcrystalline cellulose, and butylated hydroxyanisole (Example 9 did not contain butylated hydroxyanisole), excluding croscarmellose sodium, magnesium stearate, and fumaric acid, were mixed in a high-speed stirrer and kneaded with an aqueous solution (binder solution) of fumaric acid and hydroxypropyl cellulose. The kneaded mixture was dried using a vacuum dryer at room temperature and then sized into granules. The sized granules were mixed with croscarmellose sodium and magnesium stearate and made into granules for tableting, which were then compressed into tablets, thereby preparing uncoated tablets. A coating solution (coating solvent: water) was sprayed onto the prepared uncoated tablets, thereby preparing film-coated tablets.

[0087] [Table 3]ComponentsExample 9(1T / mg)Example 10(1T / mg)Example 11(1T / mg)Example 12(1T / mg)Example 13(1T / mg)Example 14(1T / mg)Example 15(1T / mg)Vonoprazan fumarate (as vonoprazan)26.72(20.00)26.72(20.00)26.72(20.00)26.72(20.00)26.72(20.00)26.72(20.00)26.72(20.00)D-Mannitol169.18169.18169.18169.18169.18169.18169.18Microcrystalline cellulose 10110.0010.0010.0010.0010.0010.0010.00Butylated hydroxyanisole00.010.10.51.01.52.0Hydroxypropyl cellulose3.003.003.003.003.003.003.00Fumaric acid0.100.100.100.100.100.100.10croscarmellose sodium3.003.003.003.003.003.003.00Magnesium stearate2.002.002.002.002.002.002.00Opadry7.007.007.007.007.007.007.00Tablet (film-coated tablet) weight221.00221.01221.10221.50222.00222.50223.00

[0088] Test Example 1. Measurement of content of N-nitroso vonoprazan in each preparation step of Examples 1 to 4

[0089] 1. Analysis method

[0090] N-nitroso vonoprazan, a nitrosamine impurity of vonoprazan, was measured by LC-MS / MS in the vonoprazan fumarate raw material used in Examples 1 to 4, the mixtures (mixtures before kneading) at each preparation process step of the film-coated tablets prepared in Examples 1 to 4, the dried granules, the uncoated tablets, and the film-coated tablets, and the results are shown in Table 5 (unit: ppm). LC-MS / MS analysis conditions are shown in Table 4 below.

[0091] <LC-MS / MS analysis conditions>

[0092] [Table 4]ColumnC18 (2.1 mm x 50 mm, 1.8 μm)Mobile phaseMobile phase A: 0.1% (v / v) formic acid in water; Mobile phase B: 0.1% (v / v) formic acid in methanolFlow rate0.4 mL / minDetector (MS / MS)ESI (positive ion mode)MRM mode (multiple reaction monitoring)N-nitroso vonoprazan (quantifier ion) 375.2 → 315

[0093] 2. Analysis results

[0094] From the results in Table 5 below, it could be confirmed that, when the tablets (film-coated tablets) were prepared through wet granulation, the formation of N-nitroso vonoprazan increased during the drying process. Specifically, the formation of N-nitroso vonoprazan in the drying process showed the largest increase in hot air circulating tray drying (increase from 0.19 ppm to 0.49 ppm in Example 1), while the formation of N-nitroso vonoprazan, a nitrosamine impurity, increased less in vacuum drying at room temperature (increase from 0.19 ppm to 0.24 ppm in Example 2) and fluidized bed drying at 50°C (increase from 0.19 ppm to 0.21 ppm in Example 3) compared to hot air circulating tray drying. It could be confirmed that vacuum drying or fluidized bed drying, in which exposure to heat during the drying process is less, are drying processes capable of forming less N-nitroso vonoprazan, a nitrosamine impurity, during the drying process compared to hot air drying. In addition, as can be seen in Example 4, it could also be confirmed that preparation of the tablets through the dry granulation method also minimized heat exposure, resulting in a process with less formation of N-nitroso vonoprazan.

[0095] [Table 5]Semi-finished product in each processExample 1Example 2Example 3Example 4Raw material0.150.150.150.15Mixture0.190.190.190.19Dried granules (hot air drying)0.49---Dried granules (vacuum drying)-0.24--Dried granules (fluidized bed drying)--0.21-Post-mixture0.510.190.200.20Uncoated tablet0.570.200.230.22Film-coated tablet0.620.260.220.23

[0096] Test Example 2. Measurement of the content of N-nitroso vonoprazan formed when the mixtures of Examples 5 to 8 were stored at 60°C for 2 weeks

[0097] 1. Analysis method

[0098] The mixtures prepared in Examples 5 to 8 were stored at 60°C for 2 weeks, and N-nitroso vonoprazan was measured by LC-MS / MS at the initial time point (week 0), week 1, and week 2. The results are shown in Table 6 and FIG. 1 (unit: ppm). LC-MS / MS analysis conditions were the same as those used in Test Example 1.

[0099] 2. Analysis results

[00100] As can be seen in Table 6 below and FIG. 1, it could be confirmed that the formation of N-nitroso vonoprazan was inhibited in Examples 6 to 8 which contained the antioxidant compared to Example 5 which did not contain the antioxidant. Surprisingly, it was confirmed that, in the case of Example 6 which contained butylated hydroxyanisole, the ability to inhibit the formation of N-nitroso vonoprazan was higher than in Examples 7 and 8 which contained butylated hydroxytoluene and propyl gallate, respectively.

[00101] [Table 6]Storage periodExample 5Example 6Example 7Example 8Initial0.220.190.190.2week 118.655.0217.4820.28 week 246.196.3838.6434.68

[00102] Test Example 3. Stress stability evaluation of tablets (film-coated tablets) containing / not containing butylated hydroxyanisole

[00103] 1. Analysis method

[00104] The tablets (film-coated tablets) prepared in Examples 9 to 15 were stored for 4 weeks under a stress stability storage condition of 60°C, and N-nitroso vonoprazan was measured by LC-MS / MS at the initial time point (week 0), week 1, and week 4. The results are shown in Table 7 and FIG. 2 (unit: ppm). LC-MS / MS analysis conditions were the same as those used in Test Example 1 above.

[00105] 2. Analysis results

[00106] As can be seen in Table 7 below and FIG. 2, it was confirmed that all cases containing butylated hydroxyanisole exhibited the effect of inhibiting the formation of N-nitroso vonoprazan under the stress stability storage condition of 60°C, and the maximum inhibitory effect was observed in tablets containing 1 mg or more of butylated hydroxyanisole per tablet (20 mg as vonoprazan). Based on these results, it can be clearly inferred that for tablets containing 10 mg of vonoprazan, the maximum inhibitory effect on N-nitroso vonoprazan formation would likewise be observed when butylated hydroxyanisole is contained at 0.5 mg or more per tablet.

[00107] [Table 7]Storage periodExample 9Example 10Example 11Example 12Example 13Example 14Example 15Initial0.440.20.210.140.150.130.14week 15.071.620.950.710.760.750.74 week 47.873.643.212.021.441.381.36

[00108] Test Example 4. Evaluation of accelerated stability of tablets (film-coated tablets) containing / not containing butylated hydroxyanisole

[00109] 1. Analysis method

[00110] The tablets (film-coated tablets) according to Examples 9 and 13 were stored in a sealed state for 6 months under accelerated stability storage conditions of 40°C / 75% RH, and the amount of N-nitroso vonoprazan was measured by LC-MS / MS (measured at the initial time point (0 months), 1 month, 3 months, and 6 months), and the results are shown in Table 8 (unit: ppm). LC-MS / MS analysis conditions were the same as those used in Test Example 1 above.

[00111] 2. Analysis results

[00112] As can be seen in Table 8 below, it could be confirmed that, under accelerated stability storage conditions of 40°C / 75% RH, the tablets (film-coated tablets) according to Example 13 which contained butylated hydroxyanisole exhibited a sufficient effect on reducing the nitrosamine impurity for up to 6 months under the accelerated conditions compared to the tablets (film-coated tablets) according to Example 9 which did not contain butylated hydroxyanisole.

[00113] [Table 8]Storage periodExample 9Example 13Initial0.440.151 month under accelerated conditions1.840.283 months under accelerated conditions2.540.376 months under accelerated conditions3.000.43

[00114] Although the present invention has been described in detail with reference to the specific features, it will be apparent to those skilled in the art that this specific description is only of a preferred embodiment thereof, and does not limit the scope of the present invention. Thus, the substantial scope of the present invention will be defined by the appended claims and equivalents thereto.

Claims

1. A pharmaceutical composition comprising vonoprazan or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the pharmaceutical composition comprises an antioxidant and inhibits the formation of N-nitroso vonoprazan, which is a nitrosamine impurity of vonoprazan.

2. The pharmaceutical composition of claim 1, wherein the antioxidant is any one or more selected from the group consisting of butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, ascorbic acid, α-tocopherol, L-cystine, glycine, and arginine.

3. The pharmaceutical composition of claim 1, wherein the antioxidant is butylated hydroxyanisole.

4. The pharmaceutical composition of claim 3, wherein the pharmaceutical composition comprises 0.01 to 2 mg of butylated hydroxyanisole per unit dosage form.

5. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a tablet or a film-coated tablet.

6. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is prepared through a wet granulation process or a dry granulation process.

7. The pharmaceutical composition of claim 6, wherein the wet granulation process comprises preparing a kneaded mixture, followed by drying using a vacuum dryer or a fluidized bed dryer.

8. A method for preparing a pharmaceutical composition comprising vonoprazan or a pharmaceutically acceptable salt thereof as an active ingredient,wherein the method for preparing the pharmaceutical composition comprises performing a wet granulation process or a dry granulation process,wherein the wet granulation process comprises preparing a kneaded mixture, followed by drying the granules using a vacuum dryer or a fluidized bed dryer.  

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